Lignan formulations

ABSTRACT

A topical formulation which includes a lignan or lignan ester in a dermatologically acceptable vehicle. The formulation can be either a cosmetic formulation or a pharmaceutical formulation.

FIELD OF THE INVENTION

This invention relates to topical formulations comprising lignans orlignan esters, either as active ingredients to improve the health and/orphysical appearance of the skin, or as preservatives or stabilizers forother active ingredients or vehicles in topical formulations.

BACKGROUND OF THE INVENTION

The publications and other materials used herein to illuminate thebackground of the invention, and in particular, cases to provideadditional details respecting the practice, are incorporated byreference.

Lignans are phenolic-compounds widely distributed in plants. They can befound in different parts (roots, leafs, stem, seeds, fruits) but mainlyin small amounts. In many sources (seeds, fruits), lignans are found asglycosidic conjugates associated with fiber component of plants. Themost common dietary sources of mammalian lignan precursors are unrefinedgrain products. The highest concentrations in edible plants have beenfound in flaxseed, followed by unrefined grain products, particularlyrye.

Considerable amounts of lignans are also found in coniferous trees. Thetype of lignans differs in different species and the amounts of lignansvary in different parts of the trees. The typical lignans in heartwoodof Norway spruce (Picea abies) are hydroxymatairesinol (HMR),alpha-conidendrin, alpha-conidendric acid, matairesinol,isolariciresinol, secoisolariciresinol, liovil, picearesinol,lariciresinol and pinoresinol (Ekman R: Distribution of lignans inNorway spruce. Acta Academiae Aboensis, Ser B, 39:1-6, 1979).

The far most abundant single component of lignans in spruce is HMR,about 60 per cent of total lignans, which occurs mainly in unconjugatedfree form. Plant lignans such as hydroxymatairesinol, matairesinol,lariciresinol and secoisolariciresinol, are converted by gut microflorato mammalian lignans, enterolactone or enterodiol. The mammalian lignanscan also be manufactured synthetically (M B Groen and J Leemhius,Tetrahedron Letters 21, 5043, 1980).

Lignans are known to possess beneficial effects on human health. Thehealth benefits obtained with lignan rich diet are, for example,decreased risk for various cancers and cardiovascular diseases(Adlercreutz (1998) Phytoestrogens and human health, In: Reproductiveand Developmental Toxicology (edited by Korach, K.). pp. 299-371, Marcel& Dekker, NY.).

Lignans, such as hydroxymatairesinol, WO 00/59946, have also beenreported to inhibit lipid peroxidation and LDL oxidation and thus beuseful as antioxidants.

Also lignans other than hydroxymatairesinol have powerful antioxidantand anti-inflammatory potential. The antioxidant action involves all themajor free radicals such as superoxide anions and peroxyl radicals (KPrasad: Antioxidant activity of secoisolariciresinol diglucoside-derivedmetabolites, secoisolariciresinol, enterodiol and enterolactone. Int JAngiology 9:220-225 (2000)).

According to studies, lignans may also prevent skin cancers (Thompson L.U. (1993): Potential health benefits and problems associated withantinutrients in foods. Food Res. Int. 26, 131-149).

No topical preparations, either for cosmetic or pharmaceutical use,comprising lignans, especially lignans which can be derived from wood ingreat quantities, or lignans or lignan derivatives, such as phenolicesters, manufactured from such wood-derivable lignans, have beendescribed in the art.

SUMMARY OF THE INVENTION

One object of the present invention is to provide topical formulationscomprising lignans or esters thereof as active ingredients, either forcosmetic or pharmaceutical use.

Another object is to provide topical formulations comprising lignans oresters thereof, active as preservatives or stabilizers for other activeingredients and/or vehicle components, wherein said formulations areuseful either as cosmetics or pharmaceuticals.

Thus, the present invention concerns a topical formulation comprising anactive agent, which is a lignan or a lignan ester, in a dermatologicallyacceptable vehicle, wherein the active agent is

-   -   i) a lignan selected from the group consisting of        hydroxymatairesinol, lariciresinol, secoisolariciresinol,        isolariciresinol, oxomatairesinol, alpha-conidendrin, liovil,        picearesinol, syringaresinol or nortrachelogenin, or    -   ii) a lignan ester of formula (I)    -   wherein L is a lignan skeleton, which optionally includes a        bridge forming a ring with one of the phenyl groups in the        formulae, and L in formula (I) is a lignan skeleton of any of        the lignans hydroxymatairesinol, matairesinol, lariciresinol,        secoisolariciresinol, isolariciresinol, oxomatairesinol,        alpha-conidendrin, pinoresinol, liovil, picearesinol,        arctigenin, syringaresinol or nortrachelogenin and L in        formula (II) is a lignan skeleton of enterodiol or        enterolactone;    -   R₁ is H or methoxy;    -   R is methyl, R′—CO— or R′—SO₂— in both of the phenyl groups        in (I) and (II) or R is H in one of the phenyl groups in (I)        or (II) and methyl, R′—CO— or R′—SO₂— in the other phenyl group;    -   wherein    -   R′ is a C₁ to C₂₂ alkyl, alkenyl, arylalkyl, aralkenyl, or an        aromatic group, and R′ is unsubstituted or substituted with one        or more hydroxy groups and/or one or more carboxyl groups, an        oxo group or an amino group,    -   or a geometric isomer or a stereoisomer thereof,    -   provided that    -   R is methyl only in a single R—O— substituent in a compound of        formula (I) where L is a skeleton of the lignan arctigenin, and    -   R is other than acetyl or propionyl if the lignan ester is a        compound of formula (II).

DETAILED DESCRIPTION OF THE INVENTION

Definitions:

A “topical formulation” refers to a composition intended to be directlylaid onto or spread on the surface of skin.

A “dermatologically acceptable vehicle” refers to excipients that aresuitable for use in direct contact with human tissues without undueadverse effects or toxicity, and that further is compatible with othercomponents in the formulation. Good aesthetic properties are also neededwhen said formulation is intended for cosmetic purposes.

“Esters” of lignans shall mean phenolic esters, where at least one, butpreferably both of the hydroxy groups in the phenols are esterified.Furthermore, the esters also include compounds where hydroxysubstituents in the lignan skeleton are esterified, in addition to theesterified hydroxy groups(s) in the phenol groups. Certain phenoliclignan esters are known in the art, namely the dibenzoate and thep-nitrodibenzoate of matairesinol; enterolactone diacetate; monoacetate,triacetate, p-hydroxymonobenzoate, and p-hydroxy-m-methoxymonobenzoateof hydroxymatairesionol; and tetraacetate and tetrabenzoate ofsecoisolariciresinol. Other phenolic diesters of lignans defined byformulas (I) or (II) have recently been disclosed in a patentapplication, PCT/FI03/00041. The international patent publication WO00/13661 discloses i.a. the lignans enterodiol, enterolactone andmatairesinol as useful ingredients in topical preparations. The patentpublications EP 38600 and EP 43150 disclose acetyl esters ofenterolactone and enterodiol, and propionyl esters of enterodiol asuseful ingredients in topical formulations.

The terms “lignans” and “lignan esters” shall also be understood tocover their glucosides.

Preferred Lignans and Lignan Esters:

As can be seen in Scheme 1, lignans bear typically two phenyl groups,which in turn are substituted with at least a hydroxy group. Anexception is the lignan arctigenin in which one of the phenolic hydroxylgroups is replaced by methoxy. Most of the lignans of formula (I) havedisubstituted phenyl groups, i.e. R₁ is H. An exception is the ryelignan syringaresinol in which R₁ is methoxy. The lignan skeleton L inthe formulae (I) and (II) stands for the part of the lignan moleculebearing such phenyl groups. In certain lignans such as isolariciresinoland conidendrin, the skeleton L includes a bridge which forms a ringwith one of the phenyl groups in the formulae. As further can be seen,many of the lignans have also one or more hydroxy groups in the skeletonL.

The lignans or esters thereof can either be derived from naturalsources, such as flaxseed, rye etc., or from wood, especially coniferouswood. Alternatively, the lignans or derivatives can be manufacturedsynthetically or by use of microbiological methods.

Especially preferred lignans are hydroxymatairesinol, lariciresinol,secoisolariciresinol and isolariciresinol and their geometric isomersand stereoisomers.

Particularly preferred lignan esters are esters of the lignans accordingto formula (I) which are hydroxymatairesinol, matairesinol,lariciresinol, secoisolariciresinol, isolariciresinol, oxomatairesinol,alpha-conidendrin, pinoresinol, liovil, picearesinol, arctigenin,syringaresinol or nortrachelogenin, or lignans of formula (II), whichare enterolactone or enterodiol.

The ester is preferable a phenolic ester, more preferable a phenolicdiester. Especially preferable are phenolic esters where the estergroups are the same.

Preferable diphenolic esters are, for example, esters of mono- ordicarboxylic fatty acids, hydroxy acids and sulfonic acids. As examplesof suitable dicarboxylic acid esters can be mentioned succinates,glutarates, and malonic acid esters. Lactic acid esters are examples ofesters with hydroxysubstituted acids. Tartaric acid and citric acidesters are examples of esters of acids with several carboxylic groupsand one or more hydroxy groups.

Particularly preferable lignan esters to be added into topicalformulations are aliphatic fatty acid diesters of lignans. Such lignanesters may be superior with regard to miscibility and dissolution intofat-based ointments. Furthermore, as more lipid soluble substances,their skin penetration is likely to be enhanced thus resulting in betterpenetration into epidermal and dermal layers of the skin. This isessential for compounds which are expected to result in anti-agingeffects, such as antioxidants.

Activity of the Lignans or Lignan Derivatives:

The lignans or lignan esters may be useful as active agents in topicalpreparations, either cosmetic or pharmaceutical preparations, especiallyas anti-aging substances for treating signs of dermatological aging,both photoaging and intrinsic aging, including skin wrinkles such asfine wrinkling in the eye area or “crows feet” or fine wrinkles aroundthe mouth area, irregular pigmentation, sallowness, loss of skinresilience and elasticity.

The lignans or esters thereof may also be useful as anti-inflammatoryagents or as skin cancer preventing agents.

The following table shows the antioxidant effect of lignans or theiresters using an in vitro model for inhibition of lipid peroxidation. Inthis model, lignan compounds were compared to the well known, potentantioxidant Trolox, which is a water-soluble derivative of vitamin E.Inhibition of lipid Test compound: peroxidation¹: Hydroxymatairesinol(HMR) 0.06 Lariciresinol 0.07 Secoisolariciresinol 0.09 α-Conidendrin0.067 Matairesinol 0.054 Nortrachelogenin 0.15 Oxomatairesinol 0.11Matairesinoibutyrate 0.35 HMR-butyrate 0.1 HMR-benzoate 0.12 Trolox 0.22¹Peroxidation of microsomal lipids initiated by tert-butylhydroperoxide,detection of peroxidation by chemiluminescence (Ahotupa M et al., Clinbiochem, 29: 139-144, 1996). Results are given as IC50-values (that is,concentration of test material that inhibits lipid peroxidation by 50%);μmol/L.

Lignans or their esters may also due to their antioxidant activity beuseful in preventing other unstable, easily oxidized constituents oftopical compositions from being auto-oxidized. Such easily oxidizedcomponents include for example omega-3 and omega-6 series fatty acidsand other fats typically present in e.g. liposomal formulations.

When used in combination with a dermatologically acceptable vehicle toform a topical formulation, the effective amount of the lignan or lignanester can be within the range from about 0.01% to about 50%, preferably0.01% to 20%. Both the effective amount and the frequency of applicationwill vary within this range based on the particular skin conditiontreated, the age and physical condition of the person under treatment,the severity of the condition, the duration of treatment, the nature ofconcurrent treatments, the specific agent or agents employed, theparticular vehicle utilized to deliver the agent or agents, and otherlike factors within the knowledge and expertise of those skilled in theart.

Preferred Formulations:

The topical formulation according to this invention can be a liquidformulation, a semisolid formulation or a foam, shampoo, spray, patch,stick, batch additive or a sponge. Preferable formulations are liquid orsemi-solid formulations.

Preferable liquid formulations for topical use are preparations of avariety of viscosities intended to be applied to the skin or nails inorder to obtain a local action or transdermal activity. They aresolutions, emulsions, micro-emulsions, lotions or suspensions which maycontain one or more active substances in a suitable vehicle. They maybe, for example, in the form of aqueous, aqueous/alcoholic or oilysolutions; dispersions of the lotion or serum type, emulsions obtainedby dispersion of a fatty phase in an aqueous phase (oil-in-water) orconversely (water-in-oil). They may also contain additional suitableantimicrobial preservatives and antioxidants as well as other excipientssuch as stabiliser, emulsifiers and thickeners.

Semi-solid formulations for topical use are intended for local ortransdermal delivery of active substance, or for their emollient orprotective action. The preparations consist of a simple or compoundbasis in which, usually, one or more active substances are dissolved ordispersed. According to its composition, the basis may influence theactivity of the preparation. Preparations may contain suitableexcipients such as antimicrobial preservatives, antioxidants,stabilisers, emulsifiers, thickeners and penetration enhancers. Severalcategories of semi-solid preparations for topical application may bedistinguished: creams, gels, ointments, pastes and poultices.

While lotions or creams can be made using conventional homogenizationmethods known to those skilled in the art, it is also possible to use aprocess of microfluidization that involves co-mixing the aqueous phaseand the oil phase of such creams and lotions in a high-pressurehomogenizer that reduces the emulsion particle size dramatically toabout 1/400 of the size of those in creams and lotions prepared withoutapplying high pressure. Microfluidization allows one to prepare elegantstable creams and lotions containing effective amounts of a lignan orlignan ester without the use of traditional emulsifiers and surfactants.

The inventive compositions can also be in the form of a multiphaseemulsion, such as a water-in-oil-in-water type emulsion as disclosed inU.S. Pat. No. 4,254,105, or oil-in-water-in silicone.

The formulations according to this invention can also be made as aliposomal formulation, for example, according to the methods describedin Mezei, J. Pharmaceut. Pharmacol., vol. 34, pp. 473-474 (1982), ormodification thereof. In such compositions, droplets of the lignan orlignan ester solution or suspension can be entrapped inside theliposomal vesicles with the shell of the liposome being a phospholipidor other suitable lipids (e.g. skin lipids). To form a topicalcomposition, the liposomes can then be added to any carrier systemdescribed above according, for example, to the preparation modes, usesand compositions of topical liposomes described in Mezei, Topics inPharmaceutical Sciences, Breimer et al. Eds., pp. 345-358, ElsevierScience Publishers BV, N.Y. (1985), or according to the reverse-phaseevaporation method described in Szoka et al., Proc. Nat. Acad. Sciences,vol. 75, pp. 4194-4198 (1978), and Diploses et al., J. Soc. CosmeticChemists, vol. 43, pp. 93-100 (1992). Lignans or lignan esters can alsobe entrapped in complexing agents, such as cyclodextrins, or polymericvesicles with a shell consisting of a suitable polymeric material, suchas gelatin, cross-linked gelatin, polyamide, poylacrylates and the like,to form a vesicle that is then incorporated into the topicalformulation.

Preferred Vehicle Components:

The aim of the vehicles is to facilitate the distribution of thecomposition when applied to the skin. Vehicles other than or in additionto water can include liquid or solid emollients, solvents, emulsifiers,humectants, thickeners, powders, surfactants, moisturizers, exfolients,stabilizers, preservatives, lubricants, chelating agents, skinpenetration enhancers, fillers, fragrances, perfumes, odor absorbers,colorants and opacifiers.

According to a preferable embodiment, the lignan or lignan ester is inthe form of an inclusion complex with a cyclodextrin.

Suitable emollients include, for example mineral oil, petrolatum,paraffin, ceresin, ozokerite, microcrystraline wax, perhydrosqualenedimethyl polysiloxanes, methylphenyl polysiloxanes, silicone-glycolcopolymers, triglyceride esters, acetylated monoglycerides, ethoxylatedglycerides, alkyl esters of fatty acids, fatty acids and alcohols,lanolin and lanolin derivatives, polyhydric alcohol esters, sterols,beeswax derivatives, polyhydric alcohols and polyethers, and amides offatty acids. Other suitable emollients can be found in Sagarin,Cosmetics, Science and Technology, 2nd Ed., vol. 1, pp. 32-43 (1972).

The emulsifiers can be cationic, anionic, nonionic, amphoteric, or acombination thereof. Nonionic emulsifiers are preferred. Exemplarynonionic emulsifiers are commercially available sorbitans, alkoxylatedfatty alcohols and alkyl polyglycosides. Anionic emulsifiers may includesoaps, alkyl sulfates, monoalkyl and dialkyl phosphates, alkylsulphonates and acyl isothionates. Other suitable emulsifiers can befound in McCutcheon, Detergents and Emulsifiers, North American Edition,pp. 317-324 (1986).

The preservatives suitable for use with the present formulations includealkanols, especially ethanol and benzyl alcohol, parabens, sorbates,urea derivatves, and isothiazolinones.

Examples of suitable thickening agents include xanthan gum, xanthan gumbrine tolerant, hydroxypropyl cellulose, hydroxyethyl cellulose,carbopol and gum acacia, Sepigel 305 (available from Seppic Co.,France), vee-gum or magnesium aluminum silicate.

As examples of suitable humectants can be mentioned urea, PCA, aminoacids, certain polyols and other compounds with hygroscopic properties.

Other Possible Active Ingredients:

The topical formulation according to the present invention may include alignan or lignan ester or their mixture as the only active ingredients.

Alternatively, the lignan or lignan ester or their mixture can also beused in combination with other active agents. Suitable other activeagents include, but are not limited to, antiseptics, antifungals,bactericides, vitamins, sunscreens, retinoids, antiallergenic agents,depigmenting agents, anti-inflammatory agents, hormones and anesthetics.

The role of the lignan or lignan ester in these formulations may be toprovide a synergistic effect in combination with the other activeingredient(s), i.e. an antioxidant, anti-inflammatory or skin cancerpreventing effect. Alternatively, the role may be to mainly serve aspreservative or stabilizer for the other active agent(s) and/orvehicles.

Particularly Suitable Vehicles in the Formulations:

a) Creams:

Water-in-oil emulsifying agents such as wool alcohols, sorbitan estersand monoglycerides.

Oil-in-water emulsifying agents such as sulphate fatty alcohols, sodiumsoaps, polysorbates, polyoxyl fatty acid and fatty alcohol esters.

b) Gels:

Lipophilic gels usually consist of liquid paraffin with polyethylene orfatty oils gelled with colloidal silica or aluminium soaps.

Hydrophilic gels consist of water, glycerol or propylene glycol gelledwith suitable gelling agents such as starch, cellulose derivates,carbomers, and magnesium-aluminium silicates.

c) Ointments:

Ointments consist of a single phase basis in which solids or liquid maybe dispersed.

Hydrophopic ointments; typical bases used for formulations are hard,liquid and light liquid paraffines, vegetable oils, animal fats,synthetic glycerides, waxes and liquid polyalkylsiloxanes.

Water-emulsifying ointments; emulsifiers: wool alcohols, Sorbian esters,monoglycerides and fatty alcohols, sulphate fatty alcohols,polysorbates, macrogol cetostearyl ether or esters of fatty acids withmacrogols.

Hydrophilic ointments; mixtures of liquid and solid macrogols

The invention will be illuminated by the following non-restrictiveExamples.

EXAMPLES

The following formulations are examples of especially preferred topicalformulations:

Example 1 Water-in-Oil Emulsion

Active substance 0.01-20%   (hydroxymatairesinol,matairesinoldibutyrate) Emulsifying agent¹  1-25% Humectant²  5-80%Preservative³ 0.01-0.5%  Water 20-50%¹such as sorbitan fatty acid esters (e.g. sorbitan sesquioleate,sorbitan monostearate, sorbitan mono-oleate, sorbitan trioleate,sorbitan tristearate, sorbitan monolaurate, sorbitan monopalmitate),wool alcohols and monoglycerides²such as glycerin, propylene glycol³such as methylparaben, ethylparaben, propylparaben, sorbic acid

Example 2 Oil-in Water Emulsion

Active substance 0.01-20%   (hydroxymatairesinol,matairesinoldibutyrate) Emulsifying agent¹  1-25% Humectant²  5-80%Preservative³ 0.01-0.5%  Water 20-50%¹such as sulphate fatty alcohols, sodium soaps, polysorbates, polyoxylfatty acids and fatty alcohol esters²such as glycerin, propylene glycol³such as methylparaben, ethylparaben, propylparaben, sorbic acid

Example 3 Gel

Active substance 0.01-1%   (hydroxymatairesinol, matairesinoldibutyrate)Gelling agent¹ 0.5-6%   Solvent² 10-45% Preservative³ Water 20-50%¹such as starch, cellulose derivatives, carbomers andmagnesium-aluminium silicates²such as ethanol, isopropanol³such as methylparaben, ethylparaben, propylparaben, sorbic acid

Example 4 Ointment

Active substance 0.01-20%  (hydroxymatairesinol, matairesinoldibutyrate)Ointment base¹  1-25% Preservative² 0.01-0.5%¹such as liquid paraffines, vegetable oils, animal fats, syntheticglycerides, macrogols²such as methylparaben, ethylparaben, propylparaben, sorbic acid

Example 5 Oil-in-Water Emulsion

Active substance 1.0% (hydroxymatairesinol, matairesinoldibutyrate)Cetostearyl alcohol 25.0% Glycerin 4.0% Glycerylmonostearate 4.8%Methylparaben 0.1% Propylparaben 0.1% Water 65.0%

Example 6 Water-in-Oil Emulsion

Active substance 1.0% (hydroxymatairesinol, matairesinoldibutyrate)Stearyl alcohol 35.0% Macrogol stearate 8.0% Propylene glycol 10.0%Mineral oil 5.0% Methylparaben 0.1% Propylparaben 0.1% Water 40.8%

Example 7 Ointment

Active substance 1.0% (hydroxymatairesinol, matairesinoldibutyrate)Petrolatum 63.8% Paraffinum liquidum 15.0% Glyceryl stearate 10.0%Propylene glycol 10.0% Sorbic acid 0.2%

Example 8 Gel

Active substance 0.1% (hydroxymatairesinol, matairesinoldibutyrate)Carbomer 3.0% Glycerin 10.0% Ethanol 33.9% Water 53.0%

It will be appreciated that the methods of the present invention can beincorporated in the form of a variety of embodiments, only a few ofwhich are disclosed herein. It will be apparent for the expert skilledin the field that other embodiments exist and do not depart from thespirit of the invention. Thus, the described embodiments areillustrative and should not be construed as restrictive.

1-9. (canceled)
 10. A topical formulation comprising an active agent,which is a lignan or a lignan ester, in a dermatologically acceptablevehicle, wherein the active agent is i) a lignan selected from the groupconsisting of hydroxymatairesinol, oxomatairesinol, alpha-conidendrin,liovil, picearesinol, or nortrachelogenin, or ii) a lignan ester offormula (I)

wherein L is a lignan skeleton, which optionally includes a bridgeforming a ring with one of the phenyl groups in the formulae, and L informula (I) is a lignan skeleton of any of the lignanshydroxymatairesinol, matairesinol, lariciresinol, secoisolariciresinol,isolariciresinol, oxomatairesinol, alpha-conidendrin, pinoresinol,liovil, picearesinol, arctigenin, syringaresinol or nortrachelogenin andL in formula (II) is a lignan skeleton of enterodiol or enterolactone;R₁ is H or methoxy; R is methyl, R′—CO— or R′—SO₂— in both of the phenylgroups in (I) and (II) or R is H in one of the phenyl groups in (I) or(II) and methyl, R′—CO— or R′—SO₂— in the other phenyl group; wherein R′is a C₁ to C₂₂ alkyl, alkenyl, arylalkyl, aralkenyl, or an aromaticgroup, and R′ is unsubstituted or substituted with one or more hydroxygroups and/or one or more carboxyl groups, an oxo group or an aminogroup, or a geometric isomer or a stereoisomer thereof, provided that Ris methyl only in a single R—O— substituent in a compound of formula (I)where L is a skeleton of the lignan arctigenin, and R is other thanacetyl or propionyl if the lignan ester is a compound of formula (II).11. The formulation according to claim 10 wherein the active agent is alignan, or a lignan ester according to formula (I).
 12. The formulationaccording to claim 10 wherein both of the groups R—O— in the lignanester compound are ester groups.
 13. The formulation according to claim12, wherein R has the same meaning in both of the R—O— groups.
 14. Theformulation according to claim 10 wherein the topical formulation is aliquid formulation, a semisolid formulation or a foam, shampoo, spray,patch, stick, batch additive or a sponge.
 15. The formulation accordingto claim 14 wherein the liquid formulation is a solution, suspension,lotion or emulsion.
 16. The formulation according to claim 14 whereinthe semisolid formulation is a cream, gel, ointment, paste or poultice.17. The formulation according to claim 10, wherein said formulation is acosmetic formulation.
 18. The formulation according to claim 10, whereinsaid formulation is a pharmaceutical formulation.